Project Summary. This proposal describes a training program for the development of the candidate's academic career in cancer biology. Throughout the period of this award, the candidate will develop her independent research program. She will also use this time to build on her scientific knowledge and mentoring skills. The candidate will be mentored by Dr. Harold Varmus, a leader in the field of cancer biology who has trained numerous successful scientists. Memorial Sloan-Kettering Cancer Center (MSKCC) will provide institutional support, including ample resources, career development activities and opportunities for interactions between scientists and clinicians to help the candidate achieve her goals. The research focuses on lung cancer, the most common cancer worldwide. The candidate has recently generated two mouse models of lung cancer based on expression of mutant Epidermal Growth Factor Receptors (EGFRs) in lung epithelial cells. She has established that the lung cancer-associated EGFR mutants can initiate lung tumorigenesis and are required for tumor maintenance. The goals of this research proposal are to determine how the phenotype and clinical behavior of EGFR mutant lung tumors are influenced by: 1) the levels of expression of EGFR;2) the presence of other EGFR family members;and, 3) cooperating genetic lesions. The specific aims are to use these new mouse models to: 1) Elucidate the mechanisms of mutant EGFR-induced transformation of lung epithelial cells;and, 2) Identify genes that cooperate with mutant EGFR in lung tumorigenesis. Findings in the mouse models will be verified in human lung cancer specimens. Relevance. EGFR mutations are found in approximately 10% of non-small cell lung cancer cases in the US and are associated with sensitivity to the tyrosine kinase inhibitors, gefitinib and erlotinib. This proposal addresses questions directly relevant to this subset of lung cancers: 1) How do the EGFR mutants transform lung cells? 2) Why do some patients who have tumors with EGFR mutations NOT respond to tyrosine kinase inhibitor treatment? 3) What are the causes of acquired resistance to tyrosine kinase inhibitor treatment?